Preparation of mannich bases

ABSTRACT

Steroidal Mannich bases are prepared by reaction of a steroid bearing an ethynyl and a hydroxy function at any of positions 3 and 17 (or 17a) with an N,N-dialkyl substituted-amino-methanol in the presence of a monovalent coinage metal ion source, e.g., cuprous chloride. The compounds are useful as pharmaceuticals and as chemical intermediates.

Unit

States Patent [1 1 Basso el air l 3, 1974 PREPARATION OF MANNICH BASES Primary Examiner-Elbert L. Roberts [75] Inventors' gzi zz ms T322135 Forge Anorney, Agent, or Firm-Gerald D. Sharkin; Richard v E. Vila; Frederick H. Weinfelclt [73] Assignee: Sandoz-Wander, Ina, Hanover,'N.J. [22] Filed: Jan. 15, 1973 57 ABSTRACT 1 Appl 0 Steroidal Mannich bases are prepared by reaction of a Related .s Application Data steroid bearing an ethyr lyl and a hydroxy function at [63] Continuation-impart of Ser. No. 162 000/ July 12 any of positions 3 and 17 Hg) with an NNidialky-l 1971. substituted-amino-methanol m the presence of a men ovalent coinage metal ion source, e.g., cuprous chlo- 52 us. ca 260/3974, 260/3975, 260/397.45, ride The compo-unds are useful as Pharmamticals 260/239.55, 260/239.5, 424/243, 424/242 and as Chemical mtermedlates'l Km. Cl. C07c 169/08, C070 169/20 26 Qhims, No Drawings Field of Search 260/2395, 239.55, 397.5

PREPARATION OF MANNICH BASES This is a continuationsin-part of copending application Ser, No. filed July 12, 1971.

This invention relate s to the preparation of K/lannich bases and more particularly to the preparation of ste- 5 roidal Mannich bases.

l-leretofore, in carrying out Mannich reactions, an

acid catalyst was employed, thus permitting competing reactions of other functionalities on the steroidal nucleus. The conventional method of avoiding such competing reactions was to block or protect such active functionalities. An advantage of the process of the present invention is that it does not employ an acid catalyst for the preparation of Mannich bases of steroids, thus a blocking or the protection of active side groups is obviated.

According to this invention, there is provided a means of introducing into a steroid at any of the three and 17 carbon atoms (or 17a, where the steroid is a D- homosteroid), both a hydroxy function and a dialk-' ylaminopropynyl radical; the dialkylaminopropynyl radical having the structure:

20 capto or unsaturation and a variety of substituents in the form of hydrocarbon radicals or functional groups conventionally employed in the steroid art, well known to impart hormonal or other endocrinological or pharmacological properties, as set forth in standard textbooks such as Steroids by Fieser and Fieser (Reinhold,

1959). The steroid moiety thus can have one or more substituents at various positions of the nucleus, taking into account the position already occupied by the amino-propynyl side chain, for example, hydroxy, meracyloxy at positions, 1,2,3,4,5,6,7,9, 11,l2,14,15,1 6 or 17; oxo at positions 1,2,3,4,6,7,1 1,12, 15,16 or 17; acetyl, hydroxy acetyl, or l-hydroxy ethyl at position 17; lower alkyl at positions 1,2,4,6,7,1 1,12, 16 or 17; or pyrazole or isoxazole rings fused to the 2-and 3-position, 'or to the 16- and 17- positions. The steroid moiety can also have one or more double bonds, especially at the l,4,5,6, 9( 10) and 9( 1 l positions. Compounds where ring A or both rings A and B are aromatic are also contemplated, in which event the amino-propynyl side chain can be present whet-as t i R independently represents hydrogen; lower alkyl having from one to four carbon atoms, e.g., methyl,-

ethyl, propyl and butyl; cycloalkyl of five to six ring R in'dependently represents hydrogen, lower'alkyl having from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; lower alkanoyl having one to six carbon atoms, e.g., formyl, acetyl, propionyl,, butyryl, isobutyryl and caproyl; cycloalkyl of five to six ring members, such as cyclopentyl, cyclohexyl and lower alkylated derivatives thereof, e.g., bearing a single alkyl group having fron one to four carbon atoms, e.g., 3-methylcyclopentyl or 4- ethylcyclohexyl; or phenyl lower alkyl in which the alkyl radical has from one to four carbon atoms, e.g., benzyl; or ii and R together form NR li and r epres ent unsubstituted or lower alkylated piperidino, pyrrolidino, hexamethylenimino, morpholino or piperazino. There can be from one to three lower-alkyl groups containing from one to four carbon atoms. The lower alkyl groups are attached to' carbon atoms except in the case of piperazino where the 4- nitro'genatom can also be alkylated. The meant;assessors;raise"istrsaaaias'ar the groups into the 3- and/or l7-(o r l7a-) position of the 1 above.

only at the 17 (or 17a) position.

I Esterfied hydroxy steroids are included within the scope of this inventionalthough the carbon content contributed by the acid moiety of the esters is not considered part of the essential carbon content of the steroid. When acyloxy radicals are present in the steroid moiety, the acyl radicals are preferably derived from carboxylic acids having from one to ten carbon atoms and molecular weights less than 200. Representative of the acyl radicals which can be present are lower alkanoyl, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like and acyloxy radicals containing a phenyl group. in acyl radicals containing a phenyl group, the latter can be unsubstituted or substituted by from one to three substituents inert under the reaction conditions used, including lower alkyl, lower alkoxy, halogen (including fluorine, chlorine, bromine and iodine) and nitro.

Thus, the invention includes the preparation of steroids atoms exclusive of ester radicals and of theomegaamine-l-lower alkynyl group and has the androstane,

l9-nor-androstane, D-homoestrane or D- homoandrostane carbon skeleton, and wherein the amino portion of the amino-l-lower alkynyl group is of j the formula NRR wherein R and R are as defined 'An embodiment of this invention is the preparation 1 of compounds of formula I which may be shown structurally as follows: i 1

wh'er'eiaTireRoam;as;iaaiaaia'maahe h araa E5 pound of the formula Ill in the presence of a coinage metal monovalent ion and may be illustrated by the following reaction scheme wherein n, R, R and R are as defined above; and M is a coinage metal, i.e., copper, silver or gold.

OH Ra l OH sl Products obtainable by the process of this invention, as represented by compounds of the formula (I) may be produced by reactively combining a corresponding steroid bearing at any of the 3- and 17- positions both a hydroxyfunction and an ethynyl radical, as represented by a compound of the formula (II), with a dialkylaminomethanol, i.e., a compound of the formula (ill) in the presence of a monovalent coinage metal ion, preferably the cuprous ion. The process may be carried out at moderate temperatures, typically in the range of 20 to C., preferably 20 to 30C., thus eliminating competing reactions of other functional groups; known to react and form a Mannich-base under conventional Mannich-conditions. The reaction may be carried out in a suitable medium. Suitable media includes inert organic solvents such as the ethers, e.g., tetrahydrofuran, diethyl ether and p-dioxane, the latter being preferred. The reaction time may vary and although, not critical, one of the important advantages of this invention over the prior art is that applicants process may be carried out in a considerably shorter period of time. in the process of the invention, cuprous salts, such as cuprous chloride, cuprous bromide, cuprous nitrate or cuprous acetate may be employed to provide cuprous ion, cuprous chloride being preferred. Generally, however, any source of copper (I) ions may be used. As examples of silver and gold salts, may be given silver or gold (I) chloride and bromide and silver nitrate. As examples of complexes of copper (I), silver and gold (I) may be given the cyanides thereof. Any source, e.g., salt, complex or adduct, may be employed which provides-the monovalent metal ions under the reaction conditions. Recovery and purification of the final product may be effected in a conventionalmanner, e.g., crystallization or column chromatography.

In 'the above describedpfocedure, the starting materials are known and may be prepared by methods described in the literature or where not known may be prepared in a manner analogous to that described in the literature for preparing the known compoundsgeg, US. Pat. No. 3,522,243 and Belgian Pat. No. 742,137.

The above described compounds I wherein R is l7a-propadienyl bearing steroids described in the literature. Thus, the compounds of formula Iaa,

in which V R is as defined above,

R signifies hydrogen or an alkanoyloxy group of two to four carbon atoms,

R" and R which may be the same or different, each Iaa signifies an alkyl group of one to three carbon atoms, 01"

. R and R together with the nitrogen atom to which they are attached, signify a pyrrolidino, piperidino,

homopiperidino or morpholino radical, and

- seven carbon atoms or an alkanoyl group of two to four carbon atoms, R represents a hydrogen atom, or a 6oz-methyl group of a 7a-methyl group, R represents hydrogen or a methyl group, and R represents hydrogen, halogen of atomic weight from 19 to 36, or a methyl group, are useful as intermediates in preparing corresponding compounds bearing l7a-propadienyl groups, by the method described in the Belgian Pat. No. 742,137 wherein the utility of such compounds is also disclosed. Compounds wherein rings A and B are represented by Z1; in which R represents hydrogen and R represents hydrogen or an alkanoyl group of two to four carbon atoms, are specifically excluded from said Belgian patent, but can be prepared analogously and are useful in the same manner as other compounds described therein where rings A and B represent Z1;

The compounds of formula lab,

Iab

in which Z. embracing rings A and B and the substituents and R8 35 defined abovfiRaI signifies a thereon, has the structure drogen atom or a methyl radical, and Ra; signifies a cycloalkyl radical having from three to a seven carbon atoms, the compounds of formula lac,

OH 1 s in which R,, R and R are as defined above, and R'bl signifies an alkyl radical of one to four-carbon atoms,

Iue

in which R,', R and R are as defined above, and ring Q, together with the substituents thereon, has

R signifies a hydrogen atom, an alkyl radical of one to four carbon atoms or an alkanoyl radical of two to four carbon atoms,

are useful as intermediates in the production'of corresponding compounds bearing l7a-propadienyl groups which are described in Belgian Pat. No. 766,147.

The compounds of formula lae,

which are described in Belgian Pat. No. 766,148.

The compounds of formulae laf and lag,

Iag

in which R,', R and R are as defined above, are

useful as intermediates in the production of corresponding compounds bearing l7a-propadienyl groups which are described in Belgian Pat. No. 767,430.

The compounds of formula lah and lai,

in which R,', R and R are as defined above, are useful as intermediates in the production of corresponding compounds bearing l7a-propadienyl groups which are described in Belgian Pat. No. 767,431.

As will be appreciated by one skilled in the art, and as described in the above-mentioned Belgian patents, the above compounds Iaa to lai may be used to obtain the l7a-propadienyl compounds; protected forms being employed where convenient. However, as is mentioned above, his an advantage of the present invention that such protected forms need not be used when carrying out the process of this invention.

Accordingly, compounds obtainable by the practice of this invention include gonene steroids of formulae Iaa, lab, lac, lad, lae, laf, lag, Iah and Iai.

Particularly useful compounds obtainable by the invention are gonene steroids of structure:

R2 st wherein R andll are as defihed above, and St signifies a gonene residue of formula wherein R is a hydrogen atom, methyl or alkanoyl having from two to four carbon atoms, e.g., acetyl propi'onyl or ri-butyl R is 0x0 or the group Particularly usetul compounds iri protected for niobtainable by this invention are gonene steroids of the structure:

wherein R is; 5561i; are as" defines assess St signifies a gonene residue of the formula wherein R four linear carbon atoms, particularly methyl, tetrahydropyran-Z-yl or tetrahydrofuran-2-yl, and k is a ketal group of the structure wherein R is an alkylenegroup having two or three car bon atoms, i.e., ethylene or propylene.

As noted above, it is a feature of this invention that the process is carried out in the absence of acid catalyst. The process is therefore carried out under nonacidic conditions. Such conditions may range from essentially neutral to moderately basic. Where any of the amino methanol reactant or the reaction product is basic, then the reaction mixture will be basic, having a pKb of, e.g., from about 7 to about 12 particularly from about 7.5 to about l0.

The invention is illustrated by the following Examples, in whichall temperatures are in degrees centigrade and room temperature to 20 to 30C., unless indicated otherwise.

EXAMPLE I i O CH:

is we; alliyl, egf, savin as? ass to 1.0 of 17a-ethynyl-l9-nor-testosterone is dissolved in 10 ml. p-dioxane and after adding 150 mgs. of CuCl the resulting suspension is stirred at room temperature for 5 minutes. Dimethylamino-methanol (1.5 ml.) is then added and the reaction mixture is stirred at room temperature for 30 minutes. The resulting solution is diluted with ml. water and extracted three times with 20 ml. methylene chloride. The combined extracts are washed with water and after drying over anhydrous sodium sulfate, evaporated to dryness in vacuo. The residue is crystallized from acetone-hexane (5:1) to obtain the title compounds m.p. l21123C. v

Carrying out the procedure of this example, but replacing the l7cz-ethynyl-l9-n0r-testosterone, i.e., 17aethynylestra-4-en-l7B-ol 3-one,- used herein with an equivalent amount of a. l7oz-ethynyl-9ot-rnethylestral-en l 7,6-ol-3-one,

Carrying out the procedure of this example, but replacing the dimethylaminomethanol used herein with an equivalent amount of a. N-pyrrolidinocarbinol or b. N-piperidinocarbinol there is similarly obtained l7a-( 3 '-N-piperidino-prop-l '-yn-1 '-yl )-estra-4- en- 1 7B-ol-3-one.

EXAMPLE Ill 3.0 g. of l7oz-ethynylestra-4,9-dien-l7fl-ol-3-one is dissolved in 30 ml. p-dioxane and after adding 300 mgs. of CuCl, the resulting suspension is stirred at room temperature for 5 minutes. Dimethylamino-methanol (4.0 ml.) is then added and the mixture is stirred at room temperature for 15 minutes, The resulting solution is diluted with 250 ml. water and extracted three times with 50 ml. methylene chloride. The combined extracts are washed with water and after drying over anhydrous sodium sulfate, evaporated to dryness in vacuo. The residue is crystallized from acetone-hexane (5:1 to obtain the title compound m.p. l50-l52C.

3 ,8523 12 l 1 32 By repeating the procedure of this example, but usvacuo. The residue is crystallized from acetone-hexane ing, in place of the cuprous chloride used therein, an (5:1) m.p. l22l23C. approximately equivalent amount of silver nitrate, the

title compound is obtained. EXAMPLE v W EXAMPLE Ill 5 cm ()H /CH:4 a.4... m "'05 ccrr -N cm M (\i/\ a \CH:

I H CH3 l 10 )M 0 C-CHz-N f I CHCl 0 I i HO HOW l7o4-[3-(1'-dimethylamino-prop-2'-ynyl)]-estr a- 1,3,5 l0)-dien-3,l7B-diol.

1.0 g. of l7a-ethynyl-e'stradiol is dissolved in 10 ml.

dimethylamino prop 2, ynyl)l esna p-dioxane and after adding 100 mgs. of CuCl, the susd at room tern erature for 5 minutes. 4,9(lO)-dien-3,l7fi-d1ol. 20 i p 250 g of 17a ethyny]estra 4,9 dien 3,17B diol is Dlemthylammomethanol (1.25 ml.) 18 then added and dissolved in 280 mL p dioxane and after adding 2.5 the mixture is stirred at room temperature. After 15 ofcucl, the suspension is Stirred for 5 minutes at room minutes crystals separate. The reaction mixture is ditemperature Dimethylaminwmethanol (370 m1) is luted with ml. water and the separated crystals are then added and the mixture is stirred at room tempera- 25 filtered washed Water and dried Crystals are ture for 20 minutes. The resulting solution is diluted crystanlzed from acemne, -P' with 1.0 litre of water and extracted three times with v EXAMPLE VI 300 ml. methylene chloride. The combined extracts are washed with water and after drying over anhydrous sodium sulfate, evaporated to dryness in vacuo. The resi- OH due is crystallized from acetone to obtain the title compound. Carrying out the procedure of this example, but replacing the l7a-ethynylestra-4,9-dien-3,l7B-diol used herein with an equivalent amount of a. l7a-ethynylestra-4,9,l l,-trien-l 7B-ol-3-one or i b. 3,3-ethylenedioxy-l7a-ethynylestra-4,9,l l-trienl7B-ol v there is similarly Obtained l7a-[3'-( l '-dimethylamino-prop-2'-ynyl)l-estraa. l7a-[3-(l' dimethylamino-prop-2-ynyl)]-estra- 40 5 1 17 1-3 n B- and 2.0 g. of l7a-ethynylestra-5(l0)-en-l7B-ol-3-one is i 1 l'dimethylaminoi dissolved in 20 ml. p-dioxane and after adding 300 mgs.- P P' YDl m nof CuCl, the suspension is stirred at room temperature EXAMPLE v for 5 minutes. Dimethylamino-methanol (3.0 ml.) is

V n then added and the mixture is stirred at room tempera- CH; ture for 20 minutes. The resulting solution is diluted 0H with 150 ml. water and extracted three times with CECCHN ml. methylene chloride. The combined extracts are 50 washed four times and after drying over anhydrous so- J dium sulfate, evaporated to dryness in vacuo to obtain the title compound.

Carrying out the procedure of this example, but re- ACO placing l7a-ethynylestra-5( l0)-en-l7B-ol-3-one used therein with an equivalent amount of 7 1 dimethy|amin0 pr0p 2I yny|)] eStra a. 5,3-ethylenedioxy-l70z-ethynylestra-5( l0),9( l l 1,3,5 10 )-trien-3, l 7B-diol-3-acetate. I dlen- 1 5- 4.5 g. of 3-ace tox'y- 1 7a-ethynylestra l ,3,5( lO)-trieny y -l B' 1713-01 is dissolved in 45 ml. p-dioxane and after adding and 300 mgs. of CuCl, the suspension is stirred at room m Y Y g 1 temperature for 5 minutes. Dimethylamino-methanol there is milarly Obtained (5.5 ml.) is then added and the mixture is stirred at W i-[ '4 i y in -p op-2'-y y .3- room temperature for 15 minutes. The resulting soluethylenedioxyeStra-5(l0),9( ien-l7B-ol, tion is diluted with 300 ml. water and is extracted three l im hylamino-prop-2-ynyl)]-3- times with 50 ml methylene chloride. The combined methoxyestra- 2,5(l0)-dien-l7fl-ol, and extracts are washed with water and after drying over c. l7a-[3'-(l-dimethylaminoprop -2'-ynyl)]-l3- anhydrous sodium sulfate,evaporated to dryness in ethylgona-4-en-l7B-ol-3-one.

of the formula EXAMPLE V11 35 g. of 17a-ethynylestra-4-en-3 ,l7B-diol is dissolved in 350 ml. of p-dioxane, and 3.5 g. of cuprous chloride, followed by 35 ml. of dimethylaminomethanol is added to the solution. The resulting mixture is stirred at room temperature for 1 hour, and is then diluted with 2.5 liters of water, resulting in separation of crystalline product which is recovered by filtration, and washed with water to obtain the title product, m.p. 93"-98"C.

What is claimed is:

l. A process for the preparation of a steroid having a carbon skeleton selected from the group consisting of androstane, and l9-nor-androst-ane, having both a B-hydroxy group and an a-omega-amino-l-propynyl group in the l7-position; wherein the steroid moiety has from 18 to 23 carbon atoms exclusive of ester radicals and of any omega-amino-l-propynyl group; and wherein the omega-amino group is of the formula NRR wherein R is amember of the group consisting of, alkyl having from one to four carbons, cycloalkyl of five to six ring members which may be unsubstituted or substituted by an alkyl having from one to four carbons and phenyl lower alkyl in which the alkyl has from one four carbons and phenyl lower alkyl in which the alkyl has from one to four carbons including compounds wherein NRR together is a member of the group con sisting of unsubstituted piperidino, pyrrolidino, hex-v amethylenimino, morpholino, piperazino, and loweralkylated piperidino, pyrrolidino, hexamethylenimino, morpholino and piperazino substituted with from one to three alkyl groups containing from one to four carbons, which comprises reacting a corresponding steroidal compound hearing at the l7-position both a B-hydroxy group and an a-ethynyl group, with a compound wherein NRR is as previously defined, in the presence of a monovalent coinage metal ion and in the absence of an acid catalyst at a temperature of from 20 to 80C.

2. A process according to claim l in which the coinage metal ion is the cuprous (I) ion.

3. A process according to claim 1 wherein the cuprous (l) ion is cuprous chloride.

d. A process according to claim 3 wherein the reaction is carried out at 20C. to 30C.

v 5. A process according to claim 3 which comprises reacting a 17ar-ethynyll9-nor-testosterone with dimethylamino-methanol in the presence of cuprous chloride producing l7ct-[3-( 1'-dimethylamino-prop-2'- ynyl ]-estra4-en- 1 75-013 -one.

s. A process according to claim 3 which comprises reacting l7ar-ethynyl-estradiol with dimethylaminomethanol in the presence of cuprous chloride producing 17a-[3( l -dimethylamino-prop-2'-ynyl)]-estra- 7. A process according to claim 3 which comprises reacting a l7oz-ethynylestra-4,9-dien-17B-ol-3-one with dimethylamino-methanol in the presence of cuprous chloride producing li-[3-( 1 -dimethylamino-prop- 2'-ynyl)]-estra-4,9( 10)dien-l 7/3-ol-3-one.

8. A process according to claim 3 which comprises reacting a l7a-ethynylestra-4,9-diene-3,17B-diol with dimethylamino-methanol in the presence of cuprous chloride producing l70z-[3-( l '-dimethylamino-prop-' 2'-ynyl)]-estra-4,9( l0)-dien-3, l 7B-diol.

9. A process according to claim 3 which comprises wherein I R" and R which may be the same or different, each signifies an alkyl group of one to three carbon atoms, or

R and R together with the nitrogen atom to which they are attached, signify a pyrrolidino, piperidino, homopiperidino or morpholino radical,

and St is a steroidal residue of formula:

the substituents g m which I 50 Ind in which R is as defined above, and ring Q, together with the substituents thereon, has

be .SFEA EE E, ,7

I R010 0- H" O clo in which R signifies a hydrogen atom, an alkyl radical of one to four carbon atoms or an alkanoyl radical of two g I to four carbon atomsgor in which v R,

R signifies a hydrogen atom, and alkyl group of one to three carbon atoms, a cycloalkyl group of five to seven carbon atoms or an alkanoyl group of two to four carbon atoms, 1

R represents a hydrogen atom, or a a-methyl group of a 7a-methyl group, he, R represents hydrogen or a methyl group, and R represents hydrogen, halogen of atomic weight i from l9 to 36, or a methyl group; 11 G l Ra; Iab

R is as defined above,

Ra signifies a hydrogen atom or a methyl radical,

and Ra signifies a cycloallcyl radical having from three to seven carbon atoms;

R1 0H H -CECCHzN .H0 m RQ,

' Iah, and

q/ f V Inc in which R is as defined above, and Rb] signifies an alkyl radical of one to four carbon atoms;

7 in which R signifies a methyl, ethyl or n-propyl group; which comprises reacting a l7a-ethynyl, 17Bhydroxy steroidal compound of the formula OH c503 in which St is as defined above, with a dialkylamino compound of the formula in which R, and R are as defined above, in the presence of a monovalent coinagemetal ion, and in the absence of an acidic catalyst at a temperature of from 20 to 80C.

12. A process for the preparation of a compound of the wherein R, and R which may be the same or different, each signifies an alkyl group of one to three carbon atoms, or v R, andR- together with the nitrogen atom to which they are attached, signify a pyrrolidino, piperidino, homopiperidino or morpholino radical,

R is methyl, ethyl or n-propyl, and

St is a gonene residue of formula:

wherein R is a hydrogen atom, methyl or alkanoyl having from two to four carbon atoms;

R is 0x0 or the group and Riot 5 a.

E 2 5 0H or -IE[,

comprising reacting an intermediate of the formula wherein R and St are as previously defined, with a dialkylamino compound of the formula in which R, and R are as previouslydefined, in the presence of a monvalent coinage metal ion, and in the absence of an acid catalyst, at a temperature of from 20 to 80C. t 13. A process of claim 12 in which. the monovalent coinage metal ion is cuprous ion.

14. A process of claim 13 in which cuprous chloride is thesource of the cuprous ion.

15. A process of claim 14 in which'the temperature is from 20 to 30C.

l6.'A process of claim 15 in which St is of formula 17. A process of claim 16 in which each of R, and R is methyl.

18. A process of claim 17 in which R;,' is methyl, R 15 s Hum:

and st is of formula (b').

119. A process for the preparation of a compound of fist wma m wherein R, and R, which may be the same or different, each signifies an alkyl group of one to three carbon atoms, or

R, and R together with the nitrogen atom to which they are attached, signify a pyrrolidino, piperidino, homopiperidino or morpholino radical,

R is methyl, ethyl or n-propyl, and

wherein R is alkyl, having from one to four linear carbon atoms, 'tetrahydropyran-2-yl or tetrahydrofuran-2-yl, and k is a ketal group of the structure as; R o 01130 wherein R is an alkylene group having two or three carbonatoms, comprising reacting an intermediate of the formula wherein R and St" are as previously defined, with a dialkylamino compound of the formula in which R and R are as previously defined, in the presence I of a monvalent coinage metal ion, and in the absence of an acid catalyst, at a temperature of from to 80C. 20. A process of claim 19 in which the monovalent coinage metal ion is cuprous ion.

21. A process of claim 20 in which cuprous chloride is the source of the cuprous ion.

22. A process of claim 21 in which the. temperature is from 20 to C.

23. A process of claim 22 in which R is methyl and R is ethylene.

24. A process of claim 23 in which St is of formula 25. A process of claim 24 in which each of R and R is methyl.

26. A process of claim 25 in which St is of formula 

1. A PROCESS FOR THE PREPARATION OF A STEROID HAVING A CARBON SKELETON SELECTED FROM THE GROUP CONSISTING OF ANDROSTANE, AND 19-NOR-ANDROSTTANE, HAVING BOTH A B-HYDROXY GROUP AND AN A-OMEGA-AMINO-1-PROPYNYL GROUP IN THE 17-POSITION GROUP AND AN THE STEROID MOIETY HAS FROM 18 TO 23 CARBON ATOMS EXCLUSIVE OF ESTER RADICALS AND OF ANY OMEGA-AMINO-1-PROPYNYL GROUP; AND WHEREIN THE OMEGA-AMINO GROUP IS OF THE FORMULA NR1R2 WHEEIN R1 IS A MEMBER OF THE GROUP CONSISTING OF, ALKYL HAVING FROM ONE TO FOUR CARBONS, CYCLOALKYL OF FIVE TO SIX RING MEMBERS WHICH MAY BE UNSUBSTITUTED OR SUBSTITUTED BY AN ALKYL HAVING FROM ONE TO FOUR CARBONS AND PHENYL LOWER ALKYL IN WHICH THE ALKYL HAS FROM ONE TO FOUR CARBONS, AND R2 IS A MEMBER OF THE GROUP CONSISTING OF, ALKYL HAVING FROM ONE TO FOUR CARBONS, CYCLOALKYL OF FIVE TO SIX RING MEMBERS WHICH MAY BE UNSUBSTITUTED OR SUBSTITUTED BY AN ALKYL HAVING FROM ONE TO FOUR CARBONS AND PHENYL LOWER ALKYL IN WHICH THE ALKYL HAS FROM ONE TO FOUR CARBON INCLUDING COMPOUNDS WHEREIN NR1R2 TOGETHER IS AS MEMBER OF THE GROUP CONSISTING OF UNSUBSTITUTED PIPERIDINO, PYRROLIDINO, HEXAMETHYLENIMINO, MORPHOLINO, PIPERAZINO, AND LOWER-ALKYLATED PIPERIDINO, SUBSTITUTED HEXAMETHYLENIMINO, MORPHOLINO AND PIPERAZINO SUBSTITUTED WITH FROM ONE TO THREE ALKYL GROUPS CONTAINING FROM ONE TO FOUR CARBONS, WHICH COMPRISES REACTING A CORRESPONDING STEROIDAL COMPOUND BEARING AT THE 17-POSITION BOTH A B-HYDROXY GROUP AND AN A-ETHYLENYL GROUP, WITH A COMPOUND OF THE FORMULA
 2. A process according to claim 1 in which the coinage metal ion is the cuprous (I) ion.
 3. A process according to claim 1 wherein the cuprous (I) ion is cuprous chloride.
 4. A process according to claim 3 wherein the reaction is carried out at 20*C. to 30*C.
 5. A process according to claim 3 which comprises reacting a 17 Alpha -ethynyl-19-nor-testosterone with dimethylamino-methanol in the presence of cuprous chloride producing 17 Alpha -(3''-(1''-dimethylamino-prop-2''-ynyl))-estra-4-en-17 Beta -ol-3-one.
 6. A process according to claim 3 which comprises reacting 17 Alpha -ethynyl-estradiol with dimethylamino-methanol in the presence of cuprous chloride producing 17 Alpha -(3''(1''-dimethylamino-prop-2''-ynyl))-estra-1,3,5(10)-trien-3,17 Beta -diol.
 7. A process according to claim 3 which comprises reacting a 17 Alpha -ethynylestra-4,9-dien-17 Beta -ol-3-one with dimethylamino-methanol in the presence of cuprous chloride producing 17 Alpha -(3''-(1''-dimethylamino-prop-2''-ynyl))-estra-4, 9(10)-dien-17 Beta -ol-3-one.
 8. A process according to claim 3 which comprises reacting a 17 Alpha -ethynylestra-4,9-diene-3,17 Beta -diol with dimethylamino-methanol in the presence of cuprous chloride producing 17 Alpha -(3''-(1''-dimethylamino-prop-2''-ynyl))-estra-4,9(10)-dien-3,17 Beta -diol.
 9. A process according to claim 3 which comprises reacting a 3-acetoxy-17 Alpha -ethynyl estra-1,3,5(10)-trien-17 Beta -ol with dimethylaminomethanol in the presence of cuprous chloride producing 17 Alpha -(3''-(1''-dimethylamino-prop-2''-ynyl))-estra-1, 3,5(10)-trien-3,17 Beta -diol-3-acetate.
 10. A process according to claim 3 which comprises reacting a 17 Alpha -ethynylestra-5(10)-en-17 Beta -ol-3-one with dimethylamino-methanol in the presence of cuprous chloride producing 17 Alpha -(3''(1''-dimethylaminoprop-2''-ynyl))-estra-5(10)-en-17 Beta -ol-3-one.
 11. A process for the preparation of a 17 Alpha -dialkaminopropynyl, 17 Beta -hydroxy steroid having the formula
 12. A process for the preparation of a compound of the formula
 13. A process of claim 12 in which the monovalent coinage metal ion is cuprous ion.
 14. A process of claim 13 in which cuprous chloride is the source of the cuprous ion.
 15. A process of claim 14 in which the temperature is from 20* to 30*C.
 16. A process of claim 15 in which St'' is of formula (a''), (b'') or (c'').
 17. A process of claim 16 in which each of R1'' and R2'' is methyl.
 18. A process of claim 17 in which R3'' is methyl, R7'' is
 19. A process for the preparation of a compound of the formula
 20. A process of claim 19 in which the monovalent coinage metal ion is cuprous ion.
 21. A process of claim 20 in which cuprous chloride is the source of the cuprous ion.
 22. A process of claim 21 in which the temperature is from 20* to 30*C.
 23. A process of claim 22 in which R5'''' is methyl and R is ethylene.
 24. A process of claim 23 in which St is of formula (a''''), (b'''') or (c'''').
 25. A process of claim 24 in which each of R1'' and R2'' is methyl.
 26. A process of claim 25 in which St is of formula (a''''). 